Phenyl Sulfonamide Research Articles

High Affinity Inhibitors of the Macrophage Infectivity Potentiator Protein from Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila─A Comparison.

Since Chagas disease, melioidosis, and Legionnaires' disease are all potentially life-threatening infections, there is an urgent need for new treatment strategies. All causative agents, Trypanosoma cruzi, Burkholderia pseudomallei, and Legionella pneumophila, express a virulence factor, the macrophage infectivity potentiator (MIP) protein, emerging as a promising new therapeutic target. Inhibition of MIP proteins having a peptidyl-prolyl isomerase activity leads to reduced viability, proliferation, and cell invasion. The affinity of a series of pipecolic acid-type MIP inhibitors was evaluated against all MIPs using a fluorescence polarization assay. The analysis of structure-activity relationships led to highly active inhibitors of MIPs of all pathogens, characterized by a one-digit nanomolar affinity for the MIPs and a very effective inhibition of their peptidyl-prolyl isomerase activity. Docking studies, molecular dynamics simulations, and quantum mechanical calculations suggest an extended σ-hole of the meta-halogenated phenyl sulfonamide to be responsible for the high affinity.

Synthesis and anti-tumor activity evaluation of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide derivatives with phenyl sulfonamide groups as potent RSK2 inhibitors.

Ribosome S6 Protein Kinase 2 (RSK2) is involved in many signal pathways such as cell growth, proliferation, survival and migration in tumors. Also, RSK2 can phosphorylate YB-1, which induces the expression of tumor initiating cells, leading to poor prognosis of triple negative breast cancer. Herein, phenyl sulfonamide was introduced to a series of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide derivatives to obtain novel RSK2 inhibitors which were evaluated RSK2 inhibitory activity and proliferation inhibitory activity against MDA-MB-468. The newly introduced sulfonamide group was observed to form a hydrogen bond with target residue LEU-74 which played crucial role in activity. The results showed that most of compounds exhibited RSK2 enzyme inhibitory with IC50 up to 1.7 nM. Compound B1 exhibited the strongest MDA-MB-468 cell anti-proliferation activity (IC50 = 0.13 μM). The invivo tumor growth inhibitory activities were evaluated with compounds B1-B3 in MDA-MB-468 xenograft model which gave up to 54.6% of TGI.

Golgi-Targeting Fluorescent Probe for Monitoring CO-Releasing Molecule-3 In Vitro and In Vivo.

CO-releasing molecule-3 (CORM-3), mainly metal carbonyl compounds, is widely used as experimental tools to deliver CO, a biological “gasotransmitter”, in mammalian systems. CORM-3 is also proposed as a potential new antimicrobial agent, which kills bacteria effectively and rapidly in vitro and in animal models. Organelle-targeting therapy, as a highly effective therapeutic strategy with little toxic and side effects, has important research significance and development prospects. Therefore, the development of effective methods for detecting and tracking CORM-3 at the subcellular level has important implications. In this paper, an easily available Golgi-targetable fluorescent probe (Golgi-Nap-CORM-3) was proposed for CORM-3 detection. In the probe Golgi-Nap-CORM-3, the phenyl sulfonamide group was selected as the Golgi-targetable unit, naphthalimide dye was chosen as a fluorophore, and the nitro group was selected as a CORM-3-responsive unit. Golgi-Nap-CORM-3 shows a CORM-3-reponsive increase of fluorescence emission at 520 nm. Using the excellent probe, the change of CORM-3 in HeLa cells, HepG2 cells, and zebrafish is successfully monitored. This study demonstrates very important information for the study of CORM-3 in vivo systems.

Design, crystal structure determination, molecular dynamic simulation and MMGBSA calculations of novel p38-alpha MAPK inhibitors for combating Alzheimer’s disease

The hallmark of the Alzheimer’s disease (AD) is the accumulation of aggregated, misfolded proteins. The cause for this accumulation is increased production of misfolded proteins and impaired clearance of them. Amyloid aggregation and tau hyperphosphorylation are the two proteinopathies which accomplish deprivation of cell and tissue hemostasis during neuropathological process of the AD, as a result of which progressive neuronal degeneration and the loss of cognitive functions. p38 mitogen-activated protein kinase (p38 MAPK) has been implicated in both the events associated with AD: tau protein phosphorylation and inflammation. p38α MAPK pathway is activated by a dual phosphorylation at Thr180 and Tyr182 residues. Clinical and preclinical evidence implicates the stress related kinase p38α MAPK as a potential neurotherapeutic target. Drug design of p38α MAPK inhibitors is mainly focused on small molecules that compete for Adenosine triphosphate in the catalytic site. Here we have carried out the synthesis of phenyl sulfonamide derivatives Sulfo (I) and Sulfo (II). Crystal structures of Sulfo (I) and Sulfo (II) were solved by direct methods using SHELXS-97. Sulfo (I) and Sulfo (II) have Rint values of 0.0283 and 0.0660, respectively, indicating good quality of crystals and investigated their ability against p38α MAPK. Docking studies revealed that the Sulfo (I) had better binding affinity (−62.24 kcal/mol) as compared to Sulfo (II) and cocrystal having binding affinity of −54.61 kcal/mol and −59.84 kcal/mol, respectively. Molecular dynamics simulation studies of Sulfo (I) and cocrystal of p38α MAPK suggest that during the course of 30 ns simulation run, compound Sulfo (I) attained stability, substantiating the consistency of its binding to p38α MAPK compared to cocrystal. Binding free energy analysis suggests that the compound Sulfo (I) is better than the cocrystal. Thus, this study corroborates the therapeutic potential of synthesized Sulfo (I) in combatting AD. Communicated by Ramaswamy H. Sarma

Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode.

Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.

Novel rhenium(V) nitride complexes with dithiocarbimate ligands – A synchrotron X-ray and DFT structural investigation

Abstract The application of rhenium complexes as therapeutic agents in nuclear medicine has propelled research into the chemistry of these compounds. In our effort to develop and investigate new therapeutic radiopharmaceuticals based on the complexes of rhenium we have investigated the nitride core, [ReN]2+. This work looks at the behavior of sulfonamide based dithiocarbimates towards the rhenium(V) nitride core. The aim here was to prepare anionic complexes with aromatic as well as fluorescent aromatic groups in the sulfonamide substituent located on the dithiocarbimate backbone. We envisaged that the polar sulfonamide and dianionic charge would confer solubility in water. Here we report the reactions of the dithiocarbimate ligands towards the rhenium(V) precursors: [ReNCl2(PPh3)2] and [ReNCl2(PMe2Ph)3]. These reactions proceeded with bis-substitution by the dithiocarbimate ligand, resulting in the formation of a dianionic rhenium(V) complex, of the type [ReN(S-S)2]2−, where (S-S) denotes the sulfonamide-tagged dithiocarbimato unit. Spectroscopic characterization data, as well as the synchrotron X-ray diffraction structure of the metal complex with the phenyl sulfonamide backbone shed light into the structural features of this interesting class of ligands and opens up opportunities for further studies in molecular imaging and therapeutic arenas.

N-alkyl-[1,1′-biphenyl]-2-sulfonamide derivatives as novel broad spectrum anti-epileptic drugs with efficacy equivalent to that of sodium valproate

In order to develop phenyl sulfonamides as a novel class of anti-epileptic drugs (AED) for both general and partial seizure, we initiated in vivo screening of our chemical library in the mice MES and sc-PTZ models and found compounds 1 and 2 as lead compounds. Optimization of 1 and 2 led to the discovery of compound 21, which showed potent anticonvulsant effect in MES, scPTZ and rat amygdala kindling models. These findings indicate that compound 21 could be a useful new broad spectrum AED like sodium valproate and provide an opportunity to struggle current therapy-resistant epilepsy.

Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4)

Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu4.

In-Silico Analysis of Chromone Containing Sulfonamide Derivatives as Human Carbonic Anhydrase Inhibitors

Computational tools of analysis were used on a set of synthetic chromone containing sulfonamide derivatives for evaluation of their enzyme inhibitory activity against Carbonic Anhydrase (CA) isozymes. GOLD docking software was utilized to dock the compounds against two human Carbonic Anhydrase (hCA) proteins; hCAII and hCA-IX. Differences in conformation and orientation of molecules within hCA-II and hCA-IX binding pockets were studied in detail which revealed that compounds with fluorine at R1 position and phenyl sulfonamide substituent at para position served as potent inhibitors against both proteins due to anomalous chemistry of fluorine atom. It was also noticed that the activity was decreased when sulfonamide moiety was shifted from para to meta position since it dragged the interacting specie of compounds away from Zn metal. Similarly, when substituents were replaced by F > Br > C2H5 > H, the activity declined due to the electronegativity effect. Binding interaction results against CA-IX seemed to be better than CA-II due to large binding cavity, predicting the more potent inhibitory activity against hCA-IX.

Synthesis and Pharmacological Evaluation of Novel Phenyl Sulfonamide Derivatives Designed as Modulators of Pulmonary Inflammatory Response

In this paper we report the design, synthesis and pharmacological evaluation of a new series of phenyl sulfonamide derivatives 2a–h and 3–8 planned by structural modification on the anti-inflammatory prototype LASSBio-468 (1). Among the synthesized analogues, the tetrafluorophthalimide LASSBio-1439 (2e) stands out showing an in vitro anti-TNF-α effect similar to the standard thalidomide. The relevance of tetrafluorination of the phthalimide nucleus was also confirmed by the anti-inflammatory profile of 2e, through oral administration, in a murine model of pulmonary inflammation. The corresponding tetrafluorocarboxyamide metabolite LASSBio-1454 (15), generated from partial hydrolysis of the derivative 2e, presented a significant in vitro effect and a pronounced anti-inflammatory activity in vivo.

Virtual screening of phenylsulfonamido-3-morpholinopropan-2-yl dihydrogen phosphate derivatives as novel inhibitors of MurC–MurF ligases from Mycobacterium leprae

Multi-drug resistance capacity for Mycobacterium leprae demands the profound need for developing new multi-targeted anti-leprosy drugs. Mur ligases (MurC, MurD, MurE, and MurF) involved in biosynthesis of bacterial cell wall peptidoglycan are the best known and validated targets for antibacterial therapy. Transition-state analogs, such as phosphonates, phosphinates, and sulfonamides have good inhibitory activity toward any one or two of these Mur ligases. With an objective of designing a better inhibitor targeting all of these four Mur ligases, we developed phenylsulfonamido-3-morpholinopropan-2-yl dihydrogen phosphate derivatives as multi-targeted small molecule inhibitors for Mur ligases and evaluated using virtual screening studies. The results suggested the 1-(3-acetyl phenyl sulfonamide)-3-morpholino propan-2-yl dihydrogen phosphate as a novel multiple inhibitor for M. leprae MurC–MurF ligases.

5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidines as novel class of potent and highly selective CaMKII inhibitors

A novel series of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines containing substituted phenyl sulfonamide are synthesized and evaluated for their inhibitory activity against CaMKII. Substituents on the phenyl group had significant impact on CaMKII inhibition, in particular, the inhibitory activity of 8p was 25-fold higher than that of KN-93, a known CaMKII inhibitor. Michaelis–Menten analysis of a representative compound suggested that the synthesized pyrimidines are calmodulin non-competitive inhibitors. Finally, 8p exhibited more than 100-fold higher selectivity for CaMKII over five types of off-target kinases.

Identification of N-(2-(azepan-1-yl)-2-phenylethyl)-benzenesulfonamides as novel inhibitors of GlyT1

A novel series of glycine transporter 1 (GlyT1) inhibitors is described. Scoping of the heterocycle moiety of hit 4-chlorobenzenesulfonamide 1 led to replacement of the piperidine with an azepane for a modest increase in potency. Phenyl sulfonamides proved superior to alkyl and non-phenyl aromatic sulfonamides, while subsequent ortho substitution of the 2-(azepan-1-yl)-2-phenylethanamine aromatic ring yielded 39 (IC 50 37 nM, solubility 14 μM), the most potent GlyT1 inhibitor in this series. Favorable brain–plasma ratios were observed for select compounds in pharmacokinetic studies to evaluate CNS penetration.

Exploration of physicochemical properties and molecular modelling studies of 2-sulfonyl-phenyl-3-phenyl-indole analogs as cyclooxygenase-2 inhibitors

In the present work, modelling study has been performed to explore the physicochemical requirements of 2-sulfonyl-phenyl-3-phenyl-indole analogs as COX-2 enzyme inhibitors. The multivariant regression expressions were developed using sequential multiple linear regression (SEQ-MLR) technique, considering adjustable correlation coefficient ( r adj 2 ). The statistical quality of SEQ-MLR equations was evaluated considering parameters like correlation coefficient ( r), standard error of estimation (SEE), and variance ratio ( F) at explicit degree of freedom (df). Orthogonality of the descriptors in SEQ-MLR was established through variance inflation factor (VIF). Developed equations have been internally validated using leave-one-out technique and further validated with test set, considering predictive squared correlation coefficient ( r pred 2 ). The orientation of the most potent and selective COX-2 inhibitor of training set, 2-(4-phenyl sulfonamide)-3-phenyl-5-methylindole, in the COX-2 active site was explored by docking. The phenyl sulfonamide moiety positioned in secondary pocket of enzyme which consists of amino acid residues Phe 518, Gln 192, Arg 513, Leu 352, Ser 353 and Val 523 is responsible for the selectivity. The unsubstituted phenyl ring positions in a hydrophobic cavity are lined by Tyr 385, Trp 387, Tyr 348, Leu 384 and Met 522. Interestingly, the indole C-5 CH 3-substituent is located in a hydrophobic region formed by Ile 345, Val 349, Ala 527, Leu 531 and Leu 534. The hydrophobic interactions of methyl group might be crucial for the potency of 2-sulfonyl-phenyl-3-phenyl-indole analogs. Study has revealed that atomic van der Waals volume and atomic masses explain COX-2 inhibitory activity of 2-sulfonyl-phenyl-3-phenyl-indole analogs significantly.

Effects of soil pH and soil water content on prosulfuron dissipation.

The sulfonylurea herbicide prosulfuron, 1-(4-methoxy-6-methyltriazin-2-yl)-3-[2-(3,3,3-trifluoropropyl)phenylsulfonyl]urea, is used for the selective control of broadleaf weeds in corn, sorghum, and cereal grains. To investigate its fate in soils, this study examined the effects of soil pH and water content on the rates of dissipation processes and the products formed under aerobic conditions. Radiometry and chromatography analyses were used to quantify the degradation products and bound residues formed in incubations of 10 different soils. The pH-dependent hydrolysis of the sulfonylurea bridge to form phenyl sulfonamide was the primary transformation process. Significant microbial degradation of prosulfuron occurred in 2 of the 10 soils, yielding (14)CO(2) and desmethyl prosulfuron among the major products. The time required for 50% dissipation of the herbicide (DT(50)) was determined for each soil and water content treatment. At equivalent water contents, prosulfuron DT(50) values were positively correlated with soil pH (P < 0.0001), varying from 6.5 days at pH 5.4 to 122.9 days at pH 7.9. Soil pH and water content strongly influence the fate of sulfonylurea herbicides in agricultural fields. Differences in the effect of soil water content on dissipation kinetics in a comparison of two soils were attributed to differences in soil pH, texture, and the ability of indigenous microorganisms to transform the herbicide.

Novel (4-Piperidin-1-yl)-phenyl Sulfonamides as Potent and Selective Human β 3 Agonists

A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human β 3-adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl sulfonamide on the left-hand side of the compounds resulted in a number of potent full agonists at the β 3 receptor. Modification of the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human β 3 agonists with low affinities for β 1- and β 2-ARs. N-Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the β 3 potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full β 3 agonist (EC 50=0.004 μM, IA=1.0) with >500-fold selectivity over β 1- and β 2-ARs.

Photodegradation of metsulfuron methyl in aqueous solution

Metsulfuron methyl (1) was effectively degraded by ultra violet light in aqueous solution. About 50% of 1 was degraded within 15 hours. A new metabolite (2) of metsulfuron methyl was isolated and characterised along with phenyl sulfonamide (3) and an unidentified photometabolite (4). The pathway of photodegradation of metsulfuron methyl has been proposed.